WO2013071067A1 - Ligands nicotiniques substitués par un phényle, et leurs procédés d'utilisation - Google Patents

Ligands nicotiniques substitués par un phényle, et leurs procédés d'utilisation Download PDF

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WO2013071067A1
WO2013071067A1 PCT/US2012/064393 US2012064393W WO2013071067A1 WO 2013071067 A1 WO2013071067 A1 WO 2013071067A1 US 2012064393 W US2012064393 W US 2012064393W WO 2013071067 A1 WO2013071067 A1 WO 2013071067A1
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compound
alkyl
vmy
hydrogen
halogen
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PCT/US2012/064393
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Milton L. Brown
Mikell A. Paige
Yingxian Xiao
Kenneth J. Kellar
Venkata Mahidhar Yenugonda
Edward D. LEVIN
Amir H. REZVANI
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Georgetown University
Duke University
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Priority to EP12847869.0A priority Critical patent/EP2776423B1/fr
Priority to US14/357,701 priority patent/US9346784B2/en
Publication of WO2013071067A1 publication Critical patent/WO2013071067A1/fr
Priority to US15/162,237 priority patent/US9994548B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • nAChRs Neuronal nicotinic acetylcholine receptors
  • CNS central nervous system
  • Sazetidine-A (Saz-A) is a recently reported new nAChR ligand that is a selective ⁇ 4 ⁇ 2 nAChR desensitizer. US Pat. No. 8,030,300 (incorporated by reference). Its major in vitro effect is to desensitize ⁇ 4 ⁇ 2 nAChRs without affecting either ⁇ 3 ⁇ 4 or a7 nAChRs. Saz-A shows strong in vivo effects in animal models, including analgesia, reduction in nicotine self-administration, reduction in alcohol intake, antidepressant-like activity, and reversal of attentional impairment.
  • the present invention is a new class of nAChR ligands that displays high selectivity and picomolar binding affinity for ⁇ 4 ⁇ 2 nicotinic receptors.
  • 11 high affinity compounds competed for [ 3 H]-epibatidine binding at ⁇ 4 ⁇ 2 receptors with K; values in the range of 0.031-0.26 nM.
  • B4067289v2 also have other medicinal and pharmacological properties that should make them good candidates as CNS drugs.
  • the selected lead compound, VMY-2-95 binds with high affinity and potently desensitizes ⁇ 4 ⁇ 2 receptors.
  • VMY-2-95 significantly reduced nicotine self-administration in rats.
  • the results support further characterization of VMY-2-95 and its analogs in animal models for developing new therapeutics to treat nicotine addiction.
  • Compounds of the invention may be useful in treating a mammal suffering from aging, addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder (ADHD), Parkinson's disease, Huntington's disease, Tourette's syndrome, amyotrophic lateral sclerosis, inflammation, stroke, spinal cord injury, dyskinesias, obsessive compulsive disorder, chemical substance abuse, alcoholism, memory deficit, pseudodementia, Ganser's syndrome, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, autism, mutism, trichtillomania, hypothermia, or disorders of sleep; or in improving cognitive functions and attention.
  • ADHD Attention
  • An aspect of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, allyl, C1-C6 alkyloxy, amino, hydroxyl, nitro, cyano, or trifluoro-Cl-C4 alkyl;
  • Ri represents hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl;
  • R 2 , R 3 , and R4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • B4067 2 89v 2 m is an integer ranging from 1 to 3; integer selected from 1 and 2; and z is an integer ranging from 0 to 5;
  • m is 1. In one embodiment n is 1. In one embodiment, z is 0. In one embodiment, z is 1. In one embodiment, z is 2.
  • R represents, independently for each occurrence, halogen, Cl- C6 alkyl, C1-C6 alkyloxy, amino, or trifluoro-Cl-C4 alkyl.
  • R represents, independently for each occurrence, halogen, methyl, methoxy, amino, or trifluoromethyl.
  • Ri is C1-C6 alkyl.
  • Ri is methyl
  • Ri is hydrogen
  • R 2 , R 3 , and R4 independently represent hydrogen.
  • An aspect of the invention is a compound of formula (II) or a pharmaceutically acceptable salt thereof
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, allyl, C1-C6 alkyloxy, amino, hydroxyl, nitro, cyano, or trifluoro-Cl-C4 alkyl;
  • Ri represents hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl
  • R 2 , R3, and R4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • Y is O, S, or N(R c );
  • R is hydrogen, CI -C6 alkyl, or allyloxycarbonyl;
  • m is an integer ranging from 1 to 3;
  • n is an integer selected from 1 and 2; and
  • z is an integer ranging from 0 to 5.
  • n is 1.
  • z is 0.
  • z is 1.
  • z is 2.
  • R represents, independently for each occurrence, halogen, Cl- C6 alkyl, C1-C6 alkyloxy, amino, or trifluoro-Cl-C4 alkyl.
  • R represents, independently for each occurrence, halogen, methyl, methoxy, amino, or trifluoromethyl.
  • Ri is C1-C6 alkyl.
  • Ri is methyl. In one embodiment Ri is hydrogen.
  • R 2 , R 3 , and R 4 independently represent hydrogen.
  • An aspect of the invention is a compound of formula (III) or a pharmaceutically acceptable salt thereof
  • Ri represents hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl
  • R 2 , R 3 , and R 4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • A represents hydrogen, halogen, methyl, C2-C6 alkyl, methoxy, hydroxy, amino, trifluoromethyl, isopropyl, or t-butyl;
  • W represents O, S, or N(R D );
  • R D represents hydrogen, C1-C6 alkyl, or allyloxycarbonyl; m is an integer ranging from 1 to 3; and n is an integer selected from 1 and 2.
  • n 1
  • n 1
  • Ri is C1-C6 alkyl.
  • Ri is methyl. In one embodiment Ri is hydrogen.
  • R 2 , R 3 , and R 4 independently represent hydrogen.
  • Y is O.
  • An aspect of the invention is a compound of formula (IV) or a pharmaceutically acceptable salt thereof
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, allyl, C 1-C6 alkyloxy, amino, hydroxyl, nitro, cyano, or trifluoro-Cl-C4 alkyl;
  • R 2 , R 3 , and R 4 independently represent hydrogen, C 1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • R h represents C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or C1-C6 alkyl substituted with at least one fluorine; m is an integer ranging from 1 to 3; and n is an integer selected from 1 and 2; and z is an integer ranging from 0 to 5. In one embodiment m is 1.
  • n 1
  • z is 0.
  • z is 1.
  • z is 2.
  • R represents, independently for each occurrence, halogen, Cl-
  • C6 alkyl C1-C6 alkyloxy, amino, or trifluoro-Cl-C4 alkyl.
  • R represents, independently for each occurrence, halogen, methyl, methoxy, amino, or trifluoromethyl.
  • R 2 , R 3 , and R4 independently represent hydrogen.
  • An aspect of the invention is a compound of formula (V) or a pharmaceutically acceptable salt thereof
  • R 2 , R 3 , and R4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • R h represents C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or C1-C6 alkyl substituted with at least one fluorine;
  • A represents hydrogen, halogen, methyl, C2-C6 alkyl, methoxy, hydroxy, amino, trifluoromethyl, isopropyl, or t-butyl;
  • W represents O, S, or N(R D );
  • R D represents hydrogen, C1-C6 alkyl, or allyloxycarbonyl; m is an integer ranging from 1 to 3; and n is an integer selected from 1 and 2. In one embodiment m is 1.
  • n 1
  • R 2 , R 3 , and R4 independently represent hydrogen.
  • An aspect of the invention is a pharmaceutical composition, comprising a compound of the invention; and a pharmaceutically acceptable carrier.
  • An aspect of the invention is a method of treating a disorder selected from the group consisting of addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder (ADHD), Parkinson's disease, Huntington's disease, Tourette's syndrome, amyotrophic lateral sclerosis, inflammation, stroke, spinal cord injury, dyskinesias, obsessive compulsive disorder, chemical substance abuse, alcoholism, memory deficit, pseudodementia, Ganser's syndrome, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, autism, mutism
  • Figure 1 depicts Scheme 1, Method B for synthesis of certain indicated compounds of the invention.
  • Figure 2 depicts Scheme 1 , Method C for synthesis of certain indicated compounds of the invention.
  • Figure 3 depicts Scheme 2 for synthesis of certain indicated compounds of the invention.
  • Figure 4 depicts Scheme 3 for synthesis of compound VMY-2-205 of the invention.
  • Figure 5 is a graph depicting acute VMY-2-95 effects on nicotine self- administration in rats .
  • Figure 6 is a graph depicting acute VMY-2-95 mean effects on nicotine self- administration in rats.
  • Figure 7 A shows selected natural and synthetic nAChR ligands.
  • B shows design strategy for VMY-2-95.
  • C shows the general structures of the present series of compounds.
  • Figure 8 shows predicted structural models of ⁇ 4 ⁇ 2 nAChR. Atomic level interactions between VMY-2-95 with ⁇ 4 ⁇ 2 nAChR are pictured. Binding site residues are labeled and shown in a stick model rendering.
  • Figure 9 Molecular modeling overlay of VMY-2-95 (colored green) with (-)- nicotine (1) varenecline (2) saz-A (3) in the ⁇ 4 ⁇ 2 nAChR binding site. Residues are labeled and shown in a stick model rendering.
  • Figure 10 shows acute VMY-2-95 effects on locomotor activity.
  • Figure 11 shows in vitro rat brain tissue protein binding data for propranolol, varenicline, sazetidine A, and VMY-2-95.
  • Figure 12 shows in vitro rat plasma protein binding data for propranolol, varenicline, sazetidine A, and VMY-2-95.
  • Figure 13 shows in vitro rat protein binding data comparing brain and plasma.
  • Figure 14 shows a comparison of binding affinities of series 1 compounds for rat nAChR subtypes with those of Saz-A, varenicline and nicotine.
  • Figure 16 shows binding affinities of series 2 compounds for rat nAChR subtypes.
  • Figure 17 shows the activation and inhibition of nAChR function by VMY-2-95, Saz-A, varenicline and nicotine.
  • Figure 18 shows the inhibition of binding by VMY-2-95 at other targets.
  • a The tested default concentration of VMY-2-95 for the primary binding assays is 10 ⁇ .
  • the value represents mean of replicates.
  • the inhibition data was generously provided by the National Institute of Mental Health; Psychoactive Drug Screening Program (NIMH PDSP). Significant inhibition is considered >50%.
  • NIMH PDSP Psychisol Screening Program
  • Significant inhibition is considered >50%.
  • Negative inhibition represents a stimulation of binding .
  • Figure 19 shows a comparison of the binding affinity (Ki) of VMY-2-95 for ⁇ 4 ⁇ 2 nAChRs with those for other targets.
  • Figure 20 shows calculated LE and physicochemical properties of compounds in series 1.
  • Figure 21 shows CHN data for final compounds in series 1-3.
  • Figure 22 shows HPLC purity data for compounds 131 and 205.
  • Nicotinic acetylcholine receptors are pentameric ligand gated ion channels with significant potential as molecular targets for the design of drugs to treat a variety of central nervous system disorders.
  • neuronal nAChR subunits In vertebrates 12 neuronal nAChR subunits have been identified, including nine alpha subunits ( ⁇ 2- 10) and three beta subunits ( ⁇ 2- ⁇ 4). These subunits may co-assemble as either heteromeric and homomeric pentameric receptors, forming a theoretically large array of receptor subtypes.
  • the predominant nAChRs in the CNS are the heteromeric ⁇ 4 ⁇ 2* subtype, composed of a4 and ⁇ 2 (the * indicates that some of these nAChRs may contain one or more other subunits as well) and the homomeric a7 subtype. Certain areas of brain also contain a high density of ⁇ 3 ⁇ 4* nAChRs, and this subtype appears to be the predominant nAChR in the autonomic nervous system.
  • Nicotine interacts with ⁇ 4 ⁇ 2, ⁇ 4 ⁇ 2 ⁇ 6* and ⁇ 7 nAChRs in the dopaminergic mesolimbic pathway, which connects the ventral tegmental area of the midbrain and the limbic system via the nucleus accumbens, and these effects of nicotine on brain dopaminergic systems are important in reinforcing drug self-administration.
  • the mesolimbic dopamine system is assumed to mediate the pleasurable and rewarding effects
  • nAChR neuropeptide kinase kinase kinase
  • nAChR neuropeptide kinase kinase kinase
  • Many of the new compounds are structurally related to the natural nAChR ligands, including nicotine, epibatidine and cytisine (FIG. 7).
  • varenicline (FIG. 7) emerged as the newest drug approved by the FDA as a therapeutic aid for smoking cessation. Clinical studies indicate that varenicline is the most effective drug currently available to help people quit smoking, but its effects may be temporary for most people. Furthermore, varenicline shows notable adverse side effects, limits the use of this compound as a therapy for smoking cessation.
  • Saz-A sazetidine- A
  • FIG. 7 We previously reported the synthesis and pharmacological properties of sazetidine- A (Saz-A) (FIG. 7), which potently and selectively desensitizes o2 containing nicotinic receptors, especially ⁇ 4 ⁇ 2 nAChRs, as measured by whole cell currents and ion efflux assays.
  • Saz-A reduced nicotine self-administration, decreased alcohol intake and improved performance in tests of attention.
  • Saz-A was also found to produce behaviors consistent with potential antidepressant and/or antianxiety effects in rats and mice.
  • saz-A is an excellent starting compound for developing additional potent and subtype-selective drugs that desensitize ⁇ 4 ⁇ 2 nAChRs.
  • Recent in vivo studies showed a low concentration of saz-A in rat brain, suggesting that optimization of saz-A physicochemical properties might enhance the in vivo CNS efficacy of this group of compounds.
  • an element means one element or more than one element.
  • agonist refers to a compound that mimics the action of natural transmitter or, when the natural transmitter is not known, causes changes at the receptor complex in the absence of other receptor ligands.
  • antagonist refers to a compound that binds to a receptor site, but does not cause any physiological changes unless another receptor ligand is present.
  • ligand refers to a compound that binds at the receptor site.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
  • alkyl refers to the radical of saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C ⁇ -C30 for straight chain, C3-C30 for branched chain), and more preferably 20 or fewer.
  • preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.
  • lower alkyl as used herein means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyls. In preferred embodiments, a substituent designated herein as alkyl is a lower alkyl.
  • aralkyl refers to an alkyl group substituted with an aryl group (e.g., an aromatic or heteroaromatic group).
  • alkenyl and alkynyl refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • aryl as used herein includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or “heteroaromatics.”
  • the aromatic ring can be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
  • ortho, meta and para apply to 1,2-, 1,3- and 1 ,4-disubstituted benzenes, respectively.
  • the names 1 ,2-dimethylbenzene and ortAo-dimethylbenzene are synonymous.
  • heterocyclyl or “heterocyclic group” refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can also be poly cycles.
  • Heterocyclyl groups include, for example, azetidine, azepine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,
  • quinolizine isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine,
  • phenanthroline phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine,
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,
  • polycyclyl or “polycyclic group” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings". Rings that are joined through non-adjacent atoms are termed "bridged" rings.
  • Each of the rings of the polycycle can be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, - CF3, -CN, or the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, sily
  • carrier refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.
  • nitro means -NO2; the term “halogen” designates -F, -CI, -Br or -I; the term “sulfhydryl” means -SH; the term “hydroxyl” means -OH; and the term “sulfonyl” means -SO2-.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety that can be represented by the general formula:
  • R9, R ⁇ Q and R' lQ each independently represent a group permitted by the rules of valence.
  • acylamino is art-recognized and refers to a moiety that
  • R 9 is as defined above, and R'j ⁇ represents a hydrogen, an alkyl, an alkenyl or -(CH2) m -Rg, where m and Rg are as defined above.
  • amino is art recognized as an amino-substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R9, R Q are as defined above.
  • Preferred embodiments of the amide will not include imides which may be unstable.
  • alkylthio refers to an alkyl group, as defined above, having a sulfur radical attached thereto.
  • the "alkylthio" moiety is represented by one of -S-alkyl, -S-alkenyl, -S-alkynyl, and -S-(CH2) m -Rg, wherein m and Rg are defined above.
  • Representative alkylthio groups include methylthio, ethyl thio, and the like.
  • carbonyl is art recognized and includes such moieties as can be represented by the general formula:
  • alkoxyl or "alkoxy” as used herein refers to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as can be represented by one of -O-alkyl, -O- alkenyl, -O-alkynyl, -0-(CH2) m -Rg, where m and Rg are described above.
  • Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, /?-toluenesulfonyl and
  • Analogous substitutions can be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.
  • each expression e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the term "substituted" is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2 nd ed.; Wiley: New York, 1991).
  • Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and ⁇ -enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis, it may be isolated using chiral chromatography methods, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • B4067289v2 Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., functioning as analgesics), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound in binding to opioid receptors.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • An aspect of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, allyl, C1-C6 alkyloxy, amino, hydroxyl, nitro, cyano, or trifluoro-Cl-C4 alkyl;
  • Ri represents hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl
  • R 2 , R 3 , and R4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine; m is an integer ranging from 1 to 3; n is an integer selected from 1 and 2; and
  • B4067 2 89v 2 z is an integer ranging from 0 to 5;
  • m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, n is 2.
  • z is 0. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 2.
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, C1-C6 alkyloxy, amino, or trifluoro-Cl-C4 alkyl.
  • R represents, independently for each occurrence, halogen, methyl, methoxy, amino, or trifluoromethyl.
  • Ri is C1-C6 alkyl.
  • Ri is methyl
  • Ri is hydrogen
  • R 2 , R 3 , and R4 independently represent hydrogen.
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, allyl, C1-C6 alkyloxy, amino, hydroxyl, nitro, cyano, or trifluoro-Cl-C4 alkyl;
  • Ri represents hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl;
  • R 2 , R 3 , and R4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • Y is O, S, or N(R c );
  • R is hydrogen, C1-C6 alkyl, or allyloxycarbonyl; m is an integer ranging from 1 to 3; n is an integer selected from 1 and 2; and z is an integer ranging from 0 to 5.
  • m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, n is 2. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 0. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 2.
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, C1-C6 alkyloxy, amino, or trifluoro-Cl-C4 alkyl.
  • R represents, independently for each occurrence, halogen, methyl, methoxy, amino, or trifluoromethyl.
  • Ri is C1-C6 alkyl.
  • Ri is methyl
  • Ri is hydrogen
  • R 2 , R 3 , and R4 independently represent hydrogen.
  • An aspect of the invention is a compound of formula (III) or a pharmaceutically acceptable salt thereof
  • Ri represents hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl
  • B4067 2 89v 2 R 2 , R 3 , and R 4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • A represents hydrogen, halogen, methyl, C2-C6 alkyl, methoxy, hydroxy, amino, trifluoromethyl, isopropyl, or t-butyl;
  • W represents O, S, or N(R D );
  • R D represents hydrogen, C1-C6 alkyl, or allyloxycarbonyl; m is an integer ranging from 1 to 3; and n is an integer selected from 1 and 2.
  • m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, n is 2.
  • Ri is C1-C6 alkyl.
  • Ri is methyl.
  • R 2 , R 3 , and R 4 independently represent hydrogen.
  • Y is O.
  • An aspect of the invention is a compound of formula (IV) or a pharmaceutically acceptable salt thereof
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, allyl, C1-C6 alkyloxy, amino, hydroxyl, nitro, cyano, or trifluoro-Cl-C4 alkyl;
  • R 2 , R 3 , and R4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • R h represents C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or C1-C6 alkyl substituted with at least one fluorine; m is an integer ranging from 1 to 3; n is an integer selected from 1 and 2; and z is an integer ranging from 0 to 5.
  • m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, n is 2.
  • z is 0. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 0. In one embodiment in accordance with any one of the foregoing
  • z is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, z is 2.
  • R represents, independently for each occurrence, halogen, C1-C6 alkyl, C1-C6 alkyloxy, amino, or trifluoro-Cl-C4 alkyl.
  • R represents, independently for each occurrence, halogen, methyl, methoxy, amino, or trifluoromethyl.
  • R 2 , R 3 , and R 4 independently represent hydrogen.
  • An aspect of the invention is a compound of formula (V) or a pharmaceutically acceptable salt thereof
  • R 2 , R 3 , and R 4 independently represent hydrogen, C1-C6 alkyl, allyl, or C3-C6 cycloalkyl, or C1-C6 alkyl substituted with at least one fluorine;
  • R represents C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or C1-C6 alkyl substituted with at least one fluorine;
  • A represents hydrogen, halogen, methyl, C2-C6 alkyl, methoxy, hydroxy, amino, trifluoromethyl, isopropyl, or t-butyl;
  • W represents O, S, or N(R D );
  • R D represents hydrogen, C1-C6 alkyl, or allyloxycarbonyl; m is an integer ranging from 1 to 3; and n is an integer selected from 1 and 2. In one embodiment, m is 1. In one embodiment, m is 2. In one embodiment, m is 3.
  • n is 1. In one embodiment in accordance with any one of the foregoing combinations of limitations, n is 2.
  • R 2 , R 3 , and R4 independently represent hydrogen.
  • R h represents C1-C6 alkyl, C3-C6 cycloalkyl, aryl, or C1-C6 alkyl substituted with 1 , 2, 3, 4, 5, or 6 fluorines.
  • An aspect of the invention is a pharmaceutical composition, comprising a compound of the invention; and a pharmaceutically acceptable carrier.
  • An aspect of the invention is a method of treating a disorder selected from the group consisting of addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder (ADHD), Parkinson's disease, Huntington's disease, Tourette's syndrome, amyotrophic lateral sclerosis, inflammation, stroke, spinal cord injury, dyskinesias, obsessive compulsive disorder,
  • a disorder selected from the group consisting of addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder (ADHD), Parkinson's disease, Huntington's disease, Tourette's syndrome, amyotrophic lateral sclerosis, inflammation, stroke, spinal cord injury, dyskinesias, obsessive comp
  • B4067 2 89v 2 chemical substance abuse alcoholism, memory deficit, pseudodementia, Ganser's syndrome, migraine pain, bulimia, premenstrual syndrome or late luteal phase syndrome, tobacco abuse, post-traumatic syndrome, social phobia, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, autism, mutism,
  • the method comprises the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.
  • the disorder is addiction.
  • the disorder is hypothermia.
  • compositions of the present invention will vary depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevented, the route of administration, and the form of the subject composition. Any of the subject formulations may be administered in a single dose or in divided doses. Dosages for the compositions of the present invention may be readily determined by techniques known to those of skill in the art or as taught herein.
  • the dosage of the subject compounds will generally be in the range of about 0.01 ng to about 10 g per kg body weight, specifically in the range of about 1 ng to about 0.1 g per kg, and more specifically in the range of about 100 ng to about 10 mg per kg.
  • administration of the formulation may need to be identified for any particular composition of the present invention. This may be accomplished by routine experiment as described herein, using one or more groups of animals (preferably at least 5 animals per group), or in human trials if appropriate.
  • the effectiveness of any subject composition and method of treatment or prevention may be assessed by administering the composition and assessing the effect of the administration by measuring one or more applicable indices, and comparing the post-treatment values of these indices to the values of the same indices prior to treatment.
  • any particular subject composition that will yield the most effective treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a subject composition, physiological condition of the patient (including age, sex, disease type and stage, general physical condition,
  • B4067289v2 responsiveness to a given dosage and type of medication may be used to optimize the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
  • the health of the patient may be monitored by measuring one or more of the relevant indices at predetermined times during the treatment period.
  • Treatment including composition, amounts, times of administration and formulation, may be optimized according to the results of such monitoring.
  • the patient may be periodically reevaluated to determine the extent of improvement by measuring the same parameters. Adjustments to the amount(s) of subject composition administered and possibly to the time of administration may be made based on these ree valuations.
  • Treatment may be initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage may be increased by small increments until the optimum therapeutic effect is attained.
  • compositions may reduce the required dosage for any individual agent contained in the compositions because the onset and duration of effect of the different agents may be complimentary.
  • Toxicity and therapeutic efficacy of subject compositions may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 and the ED 50 .
  • the data obtained from the cell culture assays and animal studies may be used in formulating a range of dosage for use in humans.
  • the dosage of any subject composition lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose may be estimated initially from cell culture assays.
  • compositions of the present invention may be administered by various means, depending on their intended use, as is well known in the art. For example, if compositions
  • B4067289v2 of the present invention are to be administered orally, they may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations or suppositories. For application by the ophthalmic mucous membrane route, compositions of the present invention may be formulated as eyedrops or eye ointments.
  • compositions may be prepared by conventional means, and, if desired, the compositions may be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • any conventional additive such as an excipient, a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent.
  • wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may be present in the formulated agents.
  • compositions may be suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of composition that may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration. Methods of preparing these formulations include the step of bringing into
  • association compositions of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association agents with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition thereof as an active ingredient.
  • Compositions of the present invention may also be administered as a bolus, electuary, or paste.
  • the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,
  • disintegrant for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose
  • Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers
  • B4067289v2 Suspensions in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • suitable non- irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for transdermal administration of a subject composition includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • compositions of the present invention may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound.
  • a non-aqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (T weens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aerosols generally are prepared from isotonic solutions.
  • compositions of this invention suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and non-aqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • kits for conveniently and effectively implementing the methods of this invention comprise any subject composition, and a means for facilitating compliance with methods of this invention.
  • Such kits provide a convenient and effective means for assuring that the subject to be treated takes the appropriate active in the correct dosage in the correct manner.
  • the compliance means of such kits includes any means which facilitates administering the actives according to a method of this invention.
  • Such compliance means include instructions, packaging, and dispensing means, and combinations thereof. Kit components may be packaged for either manual or partially or wholly automated practice of the foregoing methods. In other embodiments involving kits,
  • compositions of the present invention contemplates a kit including compositions of the present invention, and optionally instructions for their use.
  • Nicotinic acetylcholine receptors in the neuronal systems are pentameric structures composed of subunits distinct from those found in skeletal muscles. The existence of nine a-subunits (a2-al0) and three ⁇ -subunits ( ⁇ 2- ⁇ 4) in the mammalian neuronal systems has been described.
  • B4067289v2 The predominant subtype with high affinity for nicotine is comprised of three a- subunits and two ⁇ -subunits.
  • the affinity of compounds of the invention for nAChRs may be investigated in three tests for in vitro inhibition of 3 H-epibatidin binding, 3 H-a-bungarotoxin binding and 3 H-cytisine binding as described below.
  • [ 3 H]-Epibatidine Radioligand Binding Assay Stably transfected cell lines, tissue culture conditions, membrane preparation procedures and binding assays were described previously. Briefly, cultured cells at >80% confluence were removed from their flasks (80 cm 2 ) with a disposable cell scraper and placed in 10 mL of 50 mM Tris*HCl buffer (pH 7.4, 4 °C). The cell suspension was centrifuged at 10,000 x g for 5 min and the pellet was collected. The cell pellet was then homogenized in 10 mL buffer with a polytron homogenizer and centrifuged at 36,000 g for 10 min at 4 °C.
  • the membrane pellet was resuspended in fresh buffer, and aliquots of the membrane preparation were used for binding assays.
  • the concentration of [ 3 H]-epibatidine used was -500 pM for competition binding assays.
  • Nonspecific binding was assessed in parallel incubations in the presence of 300 ⁇ nicotine.
  • Bound and free ligands were separated by vacuum filtration through Whatman GF/C filters treated with 0.5% polyethylenimine. The filter-retained radioactivity was measured by liquid scintillation counting. Specific binding was defined as the difference between total binding and nonspecific binding. Data from competition binding assays were analyzed using Prism 5 (GraphPad Software, San Diego, CA).
  • Rb Efflux Assay Functional properties of compounds at nAChRs expressed in the transfected cells were measured using 80 Rb efflux assays as described previously. In brief, cells were plated into 24-well plates coated with poly-D-lysine. The plated cells were
  • B4067 2 89v 2 grown at 37 °C for 18 to 24 hour to reach 85 - 95% confluence.
  • the cells were then incubated in growth medium (0.5 mL/well) containing 86 Rb + (2 ⁇ /mL) for 4 hour at 37 °C.
  • the loading mixture was then aspirated, and the cells were washed four times with 1 mL buffer (15 mM HEPES, 140 mM NaCl, 2 mM KC1, 1 mM MgS0 4 , 1.8 mM CaCl 2 , 1 1 mM Glucose, pH 7.4).
  • 1 mL buffer 15 mM HEPES, 140 mM NaCl, 2 mM KC1, 1 mM MgS0 4 , 1.8 mM CaCl 2 , 1 1 mM Glucose, pH 7.4
  • the assay buffer was collected for measurements of 86 Rb + released from the cells.
  • Cells were then lysed by adding 1 mL of 100 mM NaOH to each well, and the lysate was collected for determination of the amount of 86 Rb + that was in the cells at the end of the efflux assay.
  • Radioactivity of assay samples and lysates was measured by liquid scintillation counting. Total loading (cpm) was calculated as the sum of the assay sample and the lysate of each well.
  • the amount of 86 Rb + efflux was expressed as a percentage of 86 Rb + loaded. Stimulated 86 Rb + efflux was defined as the difference between efflux in the presence and absence of nicotine.
  • stimulation curves were constructed in which 8 different concentrations of a ligand were included in the assay.
  • IC50(io') value inhibition curves were constructed in which 8 different concentrations of a compound were applied to cells for 10 min before 100 ⁇ nicotine was applied to measure stimulated efflux.
  • E max and ICsocio' values were determined by nonlinear least-squares regression analyses (GraphPad, San Diego, CA).
  • Binding Assays for targets Other Than nAChRS All binding assays for targets other than nACfiRs were performed by the National Institute of Mental Health's Psychoactive Drug Screening Program (PDSP) supported by NIMH grant HHSN-271-2008-00025-C (PI: Bryan Roth).
  • PDSP National Institute of Mental Health's Psychoactive Drug Screening Program
  • K determinations, receptor binding profiles, functional data, MDR1 data, etc. as appropriate
  • the predominant subtype with high affinity for nicotine is comprised of a4 and ⁇ 2 subunits.
  • nACfiRs of the latter type may selectively be labeled by the nicotine ligand 3 H-cytisine.
  • Tissue preparation may be performed at 0-4 °C unless otherwise indicated.
  • Cerebral cortices from male Wistar rats (150-250 g) may be homogenized for 20 sec in 15 mL Tris, HC1 (50 mM, pH 7.4) containing 120 mM NaCl, 5 mM KC1, 1 mM MgCl 2 and 2.5 mM CaCl 2 using an Ultra-Turrax homogenizer. The homogenate may then be centrifuged at 27,000 x g for 10 min. The supernatant may then be discarded and the pellet resuspended
  • B4067 2 89v 2 in fresh buffer and centrifuged a second time.
  • the final pellet may be resuspended in fresh buffer (35 mL per g of original tissue) and used for binding assays.
  • a-Bungarotoxin is a peptide isolated from the venom of the Elapidae snake Bungarus multicinctus and has high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a potent antagonist.
  • 3 H-a-Bungarotoxin binds to a single site in rat brain with a unique distribution pattern in rat brain.
  • nACfiR 3 H-a-Bungarotoxin labels nACfiR are formed by the l subunit isoform found in the brain and the isoform in the neuromuscular junction. Functionally, the a7 homo- oligomer expressed in oocytes has a calcium permeability greater than neuromuscular receptors and, in some instances greater than NMD A channels. Tissue Preparation. Preparations may be performed at 0-4 °C unless otherwise indicated.
  • Cerebral cortices from male Wistar rats may be homogenized for 10 sec in 15 mL 20 mM Hepes buffer containing 118 mM NaCl, 4.8 mM KC1, 1.2 mM MgS0 4 and 2.5 mM CaCl 2 (pH 7.5) using an Ultra-Turrax homogenizer. The tissue suspension may then be centrifuged at 27,000 x g for 10 min.
  • the supernatant is discarded and the pellet is washed twice by centrifugation at 27,000 x g for 10 min in 20 mL fresh buffer, and the final pellet may be resuspended in fresh buffer containing 0.01% BSA (35 mL per g of original tissue) and used for binding assays.
  • Epibatidin is an alkaloid that was first isolated from the skin of the Ecuadoran frog Epipedobates tricolor and was found to have very high affinity for neuronal nicotinic receptors, where it acts as a potent agonist. It is believed that 3 H-epibatidin binds to sites in rat brain, both of which have pharmacological profiles consistent with neuronal nicotinic receptors and a similar brain regional distribution (Hougling et al, Mol. Pharmacol. 48, 280-287 (1995)).
  • the high affinity binding sites in rat brain for 3 H-epibatidin are mainly ⁇ 4 ⁇ 2 nACfiR subtype.
  • Tissue preparation Preparations may be performed at 0-4 °C unless otherwise indicated.
  • the forebrain (cerebellum) from a male Wistar rat (150-250 g) may be homogenized for 10-20 sec in 20 mL Tris, HC1 (50 mM, pH 7.4) using an Ultra-Turrax homogenizer.
  • the tissue suspension may then be centrifuged at 27,000 x g for 10 min.
  • the supernatant is then discarded and the pellet may then be washed three times by centrifugation at 27,000 x g for 10 min in 20 mL fresh buffer, and the final pellet may be resuspended in fresh buffer (400 mL per g of original tissue) and used for binding assays.
  • B4067289v2 housed in approved standard laboratory conditions in a Duke University vivarium facility near the testing room to minimize stress induced by transporting the rats.
  • the rats were kept on a 12: 12 reverse day/night cycle, so that they were in their active phase during behavioral testing.
  • the rats in the drug iv self-administration studies were singly housed to prevent them from damaging each other's catheters.
  • the rats in the locomotor activity studies were housed in groups of 2-3. All rats were allowed access to water at all times; the rats in the nicotine-self-administration study were fed daily approximately 30 minutes after completing the sessions while those in the locomotor activity study had continuous access to food.
  • VMY-2-95 Administration.
  • VMY-2-95 was injected s.c. 10 minutes before testing in a volume of 1 mL/kg of saline.
  • the doses (0, 0.3, 1 and 3 mg/kg) were given in a counterbalanced order with at least two days between successive injections.
  • the VMY-2-95 the acute dose-effect study was tested twice while for the locomotor activity study the dose-effect function was tested once.
  • Nicotine Self- Administration Before beginning nicotine self-administration, the rats were trained for three sessions on lever pressing for food reinforcement. Then they were fitted with i.v. catheters and they received nicotine infusions (0.03 mg/kg/infusion) on an FR1 schedule for ten sessions. The rats were trained to self-administer nicotine (0.03 mg/kg/infusion, IV) via operant lever response (FR1) with a visual secondary reinforcer. Two levers were available to be pressed and only one caused the delivery of nicotine on an FR1 schedule. Pressing the lever on the active side resulted in the activation of the feedback tone for 0.5 second and the immediate delivery of one 50- ⁇ 1 infusion of nicotine in less than 1 second. Each infusion was immediately followed by a one-minute period in which the cue lights went out, the house light came on and responses were recorded but not reinforced.
  • the repeated measures were VMY-2-95 dose and the repeated administration of each dose. Significant interactions were followed up by tests of the simple main effects. Alpha of p ⁇ 0.05 (two-tailed) was used as the threshold for significance.
  • the reaction mixture was quenched with saturated NH 4 C1 solution and extracted with CH 2 C1 2 .
  • the combined organic layers were washed with 2 N HC1, water and saturated NaCl solution.
  • the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product.
  • the crude product was purified by column chromatography. See FIG. 1.
  • reverse phase HPLC was performed on Restek's Ultra IBD CI 8 (5 ⁇ , 4.6 x 50 mm) using two Shimadzu LC-20AD pumps and a SPD-20A-vis detector set at 330 nm: Method A, 10%-40% acetonitrile in H 2 0 (v/v), flow rate at 1 mL/min over 20 min; method B, 8%-40% methanol in H 2 0 (v/v), flow rate at 1 mL/min over 20 min.
  • reverse phase HPLC was performed on Restek's Ultra IBD C 18 (5 ⁇ , 4.6 x 50 mm) using two Shimadzu LC-20AD pumps and a SPD-20A-vis detector set at 330 nm: Method A, 10%-40% acetonitrile in H 2 0 (v/v), flow rate at 1 mL/min over 20 min; method B, 8%-40% methanol in H 2 0 (v/v), flow rate at 1 mL/min over 20 min.
  • VMY-2-191 (R)-3-(azetidin-2-ylmethoxy)-5-(phenylethynyl)pyridine (VMY-2-191): Method
  • Example 36 (S)-3-(azetidin-2-ylmethoxy)-5-phenylpyridine (VMY-2-203): This compound was prepared according to the method shown in FIG. 3. To a solution of (5)-tert-butyl-2- ((5-bromopyridin-3-yloxy)methyl)azetidine-l-carboxylate (1, 0.58 mmol) in 9 mL of toluene and 3 mL of ethanol was added phenyl boronic acid (0.69 mmol) followed by 2 mL of 2 M Na 2 C0 3 and tetrakis(triphenylphosphine)palladium (0) (0.03 mmol).
  • the in vitro binding affinities of the new ligands were measured for defined receptor subtypes ( ⁇ 2 ⁇ 2, ⁇ 2 ⁇ 4, ⁇ 3 ⁇ 2, ⁇ 3 ⁇ 4, ⁇ 4 ⁇ 2, ⁇ 4 ⁇ 4, ⁇ 6 ⁇ 2, ⁇ 6 ⁇ 4, and ⁇ 7) expressed in stably transfected cell lines.
  • [ 3 H]Epibatidine ([ 3 H]EB) binds to the agonist recognition site of all of the defined receptor subtypes with high affinities.
  • Rat forebrain homogenates were included to allow comparison between the heterologous and native ⁇ 4 ⁇ 2 and al nACfiRs. See FIG. 18 for binding affinity values ( ⁇ ;) of the ligands at the three major nAChR subtypes ( ⁇ 3 ⁇ 4, ⁇ 4 ⁇ 2, and a7).
  • Functional properties of the new ligands were determined by 86 Rb + efflux assays in cells expressing ⁇ 3 ⁇ 4 and ⁇ 4 ⁇ 2 nAChR subtypes. Functional activity of each new ligand was measured in terms of its agonism, antagonism and desensitization ability.
  • Agonist activity of each of the ligands was tested at eight concentrations. The responses were compared to that stimulated by 100 ⁇ (-)-nicotine, a near maximally effective concentration. The full concentration-effect curves generated potency (EC 50 ) and efficacy (E max ) of each ligand. The antagonist activity of each new compound was determined by applying the compound to cells simultaneously with 100 ⁇ (-)-nicotine.
  • each compound was tested for antagonist activity at eight concentrations.
  • the potency (ICso(o')) of each ligand as an antagonist was derived from the full concentration- effect curves.
  • the desensitization potency of each ligand was determined by pre-treating cells with the test compound for 10 minutes before 100 ⁇ (-)-nicotine was applied.
  • B4067289v2 potency of a compound to desensitize the receptor after a 10 minute exposure was obtained with full concentration-effect curves using at least eight concentrations of the ligand.
  • IC 50(10') concentration-effect curves using at least eight concentrations of the ligand.
  • 86 Rb + efflux assays were the main methodology used to determine functional properties, whole-cell current measurements were also used to verify the key experiments. See Table 1 for potency of the compounds to desensitize the two major receptor (IC 50(10') ) subtypes, ⁇ 3 ⁇ 4 and ⁇ 4 ⁇ 2.
  • VMY-2-95 Animals had an initial ten session of nicotine (0.03 mg/kg FRI) self-administration prior to VMY-2- 95 delivery.
  • VMY-2-95 was delivered with acute sc injections 10 minutes before the start of 45 minute nicotine sessions in a repeated measures counterbalanced design at one of three doses: 0.3, 1, and 3 mk kg, or saline vehicle.
  • Alpha of p ⁇ 0.05 (two-tailed) was used as the threshold for significance. Results are shown in FIG. 5 and FIG. 6.
  • VMY-2-95 showed similar potency as Sazetidine-A. The effect of VMY-2-95 appeared to become more pronounced during the second phase (see FIG. 5).
  • the SHAKE algorithm was used to keep all bonds involving hydrogen atoms rigid. Weak coupling temperature and pressure coupling algorithms were used to maintain constant temperature and pressure, respectively. Electrostatic interactions were calculated with the Ewald particle mesh method with a dielectric constant at lRy and a nonbonded cutoff of 12 A for the real part of electrostatic interactions and for van der Waals interactions. The total charge of the system was neutralized by addition of a chloride ion. The system was solvated in a 12 A cubic box of water where the TIP3P model was used. 5000 steps of minimization of the system were performed in which the ⁇ 4 ⁇ 2 nACfiR was constrained by a force constant of 75 kcal/mol/A.
  • Binding Affinities for nAChR Subtypes The binding affinities of all compounds synthesized for the receptor subtypes were examined in binding competition studies against
  • All compounds in series 1 exhibited high affinity for the rat ⁇ 4 ⁇ 2 nAChR subtype with K; values ranging from 0.031 nM (VMY-2-131) to 0.26 nM (VMY-2-117). These compounds also showed high affinities for the two other subtypes containing ⁇ 2 subunits, ⁇ 2 ⁇ 2 and ⁇ 3 ⁇ 2 nAChRs. In contrast, the binding affinities of these compounds for nAChR subtypes containing ⁇ 4 subunits are much lower than those for their ⁇ 2 containing counterparts. As shown in FIG.
  • VMY-2-95 showed a promising binding profile
  • These singly substituted analogs have binding profiles similar to that of VMY-2-95 (FIG. 14).
  • the dual substituted analogs, VMY-2-113, 131, 135 and 139 also showed high affinities and selectivity for ⁇ 4 ⁇ 2 receptors.
  • the installation of CF 3 at position 3 decreased the binding affinity for the ⁇ 4 ⁇ 2 receptor, as shown by the binding profile of VMY-2-117.
  • VMY-2-161 azetidine replace with cyclobutane
  • VMY-2-177 ring opened analogue of azetidine
  • VMY-2-191 azetidine ring is important for the high affinity and selectivity binding profile.
  • VMY-2-191 which is the (i?)-form of VMY-2-95, was synthesized.
  • the binding profile of VMY-2-191 is similar to that of VMY-2-95, though VMY-2-191 has a slightly lower affinity for ⁇ 4 ⁇ 2 receptors than VMY-2-95.
  • Binding Affinities for targets Other Than nAChRs To determine affinities of the lead compound, VMY-2-95, for targets other than neuronal nAChRs, we tested VMY-2-95 in binding assays using 41 other targets, including many CNS receptors and transporters. As shown in FIG. 18, the preliminary binding assays using a single concentration of VMY-2- 95 at 10 ⁇ generated 32 "miss" (less than 50% inhibition of bindings by specific labeled
  • the Ki values of VMY-2-95 at these 9 targets were determined by performing secondary binding assays using a series of concentrations of VMY-2-95. As shown in FIG. 19, the compound has low binding affinities for these targets. Furthermore, the binding affinity of VMY-2-95 for ⁇ 4 ⁇ 2 nAChRs is at least 3,000 times higher than that for any of those 9 targets.
  • VMY-2-95 Effects of VMY-2-95 on Functions of nAChRs
  • the functional effect of the lead compound, VMY-2-95 was assessed by measuring agonist- stimulated 86 Rb + efflux from stably transfected cells expressing nAChRs, either human ⁇ 4 ⁇ 2 subtype or rat ⁇ 3 ⁇ 4 subtype. Its ability to desensitize nAChRs was determined by measuring nicotine- stimulated 86 Rb + efflux after cells were preincubated with VMY-2-95 for 10 min. For comparison, we also examined three other nicotinic ligands in the same manner, Sazetidine- A, varenicline and (-)-nicotine.
  • VMY-2-95 did not show any detectable agonist activity at rat ⁇ 3 ⁇ 4 nAChRs.
  • the compound showed clear agonist activity with EC50 value as 8.6 nM.
  • its efficacy for activating the ⁇ 4 ⁇ 2 receptors is very low, only 26% of the maximal stimulation by nicotine.
  • varenicline showed near- full agonist activity at ⁇ 3 ⁇ 4 nAChRs but partial agonist activity at ⁇ 4 ⁇ 2 receptors.
  • VMY-2-95 potently desensitized ⁇ 4 ⁇ 2 receptor function with an IC 50(10") value of 16 nM, which is similar to that of Sazetidine-A but significantly lower than those of varenicline and nicotine.
  • the IC 50(10 " ) value of VMY-2-95 in desensitizing ⁇ 3 ⁇ 4 nAChRs was higher than 10,000 nM, which is more than 600 times higher than its IC 50(10") value in desensitizing ⁇ 4 ⁇ 2 nAChRs.
  • VMY-2-95 Effects of VMY-2-95 on Nicotine Self- Administration in Rats.
  • VMY-2-95 significantly (F(3,42) 3.36, p ⁇ 0.05) decreased intravenous nicotine self-administration in a dose-dependent manner.
  • VMY-2-95 did not produce significant effects.
  • VMY-2-95 for targets other than neuronal nAChRs, we tested VMY-2-95 in binding assays using 41 other targets, including many CNS receptors and transporters.
  • the preliminary binding assays using a single concentration of VMY-2-95 at 10 ⁇ generated 32 "miss" (less than 50% inhibition of bindings by specific labeled ligands) and 9 "hit” (more than 50% inhibition of bindings).
  • the K; values of VMY-2-95 at these 9 targets were determined by performing secondary binding assays using a series of concentrations of VMY-2-95.
  • the compound has low binding affinities for these targets.
  • the binding affinity of VMY-2-95 for ⁇ 4 ⁇ 2 nAChRs is at least 3,000 times higher than that for any of those 9 targets.
  • the docked positions of compounds were remodeled using a step-by-step manual docking methodology with restrained molecular dynamics (MD) simulations followed by energy minimization.
  • MD restrained molecular dynamics
  • the optimum van der Waals and H-bond distance constraints was set between the ligand and the ⁇ 4 ⁇ 2 nACfiR ligand binding domain residues.
  • the final binding complex is depicted in FIG. 8 and 9.
  • VMY-2-95, (-)-nicotine, varenicline and Saz-A are buried at the aromatic rich residues such as W147a, W55p, Y91a, Y188a, Y195a, and F117p (FIG. 8 and 9) and
  • B4067289v2 occupied a similar binding region.
  • the relative orientations of the compounds in the ⁇ 4 ⁇ 2 nAChR binding site were slightly different. This may be due to conformational adjustments inside the binding site.
  • the azetidine group in saz-A and VMY-2-95 forms stacking interactions with the amino acid W147a (FIG. 8 and 9).
  • the pyridine ring occupies a slightly different position to compensate for the conformational entropy penalty due to isomeric constraints.
  • the hydroxy group of saz-A forms a hydrogen bond with Y188a whereas this residue forms hydrogen bond with the pyrazine ring nitrogen of varenicline, and this hydrogen bond is absent in (-)-nicotine.
  • VMY-2-95, and saz-A have hydrophobic groups extending from the pyridine ring, forming additional favorable hydrophobic interactions with ⁇ 76 ⁇ , ⁇ 77 ⁇ , ⁇ 112 ⁇ , ⁇ 09 ⁇ , F117p, and L119p. These interactions can be compared with the interactions of varenicline involving ⁇ 09 ⁇ , Fl 17 ⁇ , and LI 19 ⁇ (FIG. 8 and 9).
  • the benzene ring of the ethynylbenzene of VMY-2-95 form a stronger stacking and lipophilic interaction with ⁇ 76 ⁇ , ⁇ 77 ⁇ , ⁇ 112 ⁇ , and ⁇ 09 ⁇ than the corresponding hex-5-yn-l-ol group of saz-A.
  • the 3-(2-phenylethynyl) pyridine group of VMY- 2-95 is more rigid and may require a smaller penalty in conformational entropy as compared to the flexible 6-(3-pyridyl) hex-5-yn-l-ol group of saz-A (FIG.
  • BBB blood-brain barrier
  • PSA polar surface area
  • ClogP lipophilicity
  • CNS drugs have a MW ⁇ 450-Da. All the compounds in this report will have molecular weights less than 450 Da. In addition, all these compounds have clogP values ⁇ 5, suggesting a reasonable probability of good oral absorption and intestinal permeability.
  • a Polar surface area (PSA) less than 60 A 2 is predictive for a compound to penetrate BBB well. As shown in FIG. 20, all the compounds in series 1 have PSA values smaller than 60 A 2 .
  • Ligand efficiency is an important metric in drug discovery and has been used to measure the relationship of biological activity (affinity) with molecular size. LE is the ratio of the free energy of binding over the number of heavy atoms in a molecule. LE is a useful optimization tool to evaluate a ligand's ability to effectively bind to the targeted protein. Considering the binding affinity (Ki) of the compounds in series 1, we calculated the LE. All compounds in series 1 have a LE value in the range of 0.7 kcal/mole (a LE >0.3 is favorable, FIG. 20) and suggest that these compounds are optimized for receptor occupancy.
  • varenicline Chodet ®
  • varenicline is considered superior in terms of relative efficacy.
  • the percentage of subjects who remained smoke-free for 12 months following treatment with varenicline fell to -22%.
  • varenicline appears to be safe for most people, exacerbation of schizophrenia and manic episodes associated with treatment with varenicline have been reported.
  • varenicline may be associated with increased adverse cardiovascular events, including angina and heart attack. More commonly, nearly 30% of participants taking varenicline in clinical trials reported nausea and 18%) reported vomiting.
  • varenicline was developed as a partial agonist at ⁇ 4 ⁇ 2 nACfiRs, it is also nearly a full agonist at ⁇ 3 ⁇ 4 nACfiRs, which predominate in autonomic ganglia and brainstem autonomic centers, as well as at a7 nAChRs, another important subtype in brain. More recently, varenicline was found to be a potent agonist of the human 5-hydroxytryptamine3 receptors (5-HT 3 ). The side effects of varenicline are most likely to be mediated through its actions at receptors other than ⁇ 4 ⁇ 2 nAChRs, including ⁇ 3 ⁇ 4* nAChRs, l nACfiRS and 5- HT 3 receptors.
  • Saz-A is a novel nACfiR ligand that is highly selective for ⁇ 4 ⁇ 2 receptors. In binding assays, Saz-A has a much higher binding affinity for ⁇ 4 ⁇ 2 nAChRs than for ⁇ 3 ⁇ 4 or a7 receptors.
  • VMY-2-95 and other compounds in series 1 have more favorable values of physicochemistry parameters, such as lower PSA and higher clogP than those of Saz-A, indicating the possibility that they may have better BBB penetration and higher brain distribution.
  • B4067289v2 significantly reduces nicotine self-administration at 3 mg/kg in the rat model, showing promise as a smoking cessation aid.
  • the binding model of ⁇ 4 ⁇ 2 nACfiR with VMY-2-95 suggests similar occupancy of the binding pocket as that of nicotine and varenicline. Moreover, the phenylethynyl group at C-5 position of pyridine in VMY-2-95 occupies a potentially critical space in the pocket and forms favorable hydrophobic interactions with ⁇ 4 ⁇ 2 nACfiR (FIG. 8 and 9).
  • VMY-2-95 does not have high binding affinity for any of these targets.
  • the compound either is not a "hit” in primary binding assays, or showing at least 3,000-fold lower binding affinities than that for ⁇ 4 ⁇ 2 nAChRs in secondary binding assays (FIG. 19,). It is important to note that VMY-2 - 95 is not a "hit” at 5-HT 3 receptors, which mediate some of varenicline's adverse side effects, including nausea.

Abstract

Cette invention concerne des composés et des procédés pour les utiliser dans le but de traiter un trouble choisi dans le groupe constitué par l'addiction, la douleur, l'obésité, la schizophrénie, l'épilepsie, la manie et la maniacodépression, l'anxiété, la maladie d'Alzheimer, les troubles de l'apprentissage, le déficit des fonctions cognitives, le déficit de l'attention, la perte de mémoire, la démence à corps de Lewy, le trouble du déficit de l'attention avec hyperactivité (TDAH), la maladie de Parkinson, la maladie d'Huntington, le syndrome de Tourette, la sclérose latérale amyotrophique, l'inflammation, l'ACV, la lésion de la moelle épinière, les dyskinésies, les troubles obsessionnels compulsifs, l'abus de substances chimiques, l'alcoolisme, le trouble de la mémoire, la pseudo-démence, le syndrome de Ganser, la douleur migraineuse, la boulimie, le syndrome prémenstruel ou syndrome de la phase lutéale tardive, le tabagisme, le syndrome post-traumatique, la phobie sociale, le syndrome de fatigue chronique, l'éjaculation précoce, les troubles de l'érection, l'anorexie nerveuse, l'autisme, le mutisme, la trichotillomanie, l'hypothermie, et les troubles du sommeil.
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